Crystal modification A of 8-cyano-1-cyclopropyl-7-(is,6s-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

ABSTRACT

The present invention relates to a defined crystal modification of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0] nonan-8-yl)-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I), to processes for its preparation and to its use in pharmaceutical preparations.                    
     The crystal modification can be distinguished from other crystal modifications of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl )-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) by its characteristic X-ray powder diffractogram and its differential thermodiagram (see description).

This application is the 371 of PCT/EP99/08775 filed on Nov. 15, 1999.

The present invention relates to a defined crystal modification of8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, to processes for itspreparation and to its use in pharmaceutical preparations.

Hereinbelow,8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula(I) is referred to as CCDC.

CCDC is known from DE-A 19 633 805 or PCT AppI. No. 97 903 260.4.According to these publications, it is prepared by reacting7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid with (1S,6S)-2,8-diaza-bicyclo[4.3.0]nonane in a mixture ofdimethylformamide and acetonitrile in the presence of an auxiliary base.Water is added to the mixture and CCDC is then extracted from waterusing dichloromethane and is isolated by removing the extractant. Thisgives a powder whose crystal modification is not unambiguous. On thecontrary, the powder is largely amorphous and can contain mixtures ofdifferent crystal modifications. If, by chance, a uniform crystalmodification is formed, it is not clear how it can be extracted andobtained in a defined form. However, it is the precondition forpreparing medicaments that, for an active compound which can be presentin different crystal modifications, it can be stated unambiguously whichof its crystal modifications is used for preparing the agent.

The partially amorphous powder, which is obtained by the preparationprocess outlined above, is furthermore hygroscopic. Amorphous solids,and in particular hygroscopic solids, are difficult to handle when beingprocessed pharmaceutically since, for example, they may have low bulkdensities and unsatisfactory flow properties. Moreover, the handling ofhygroscopic solids requires special work techniques and apparatuses toobtain reproducible results, for example with respect to the activecompound content or the stability of the solid formulations produced.

It is therefore an object of the invention to prepare a crystalline formof a defined modification of CCDC which, owing to its physicalproperties, in particular its crystal properties and its behaviourtowards water, is easy to handle in pharmaceutical formulations.

This object is achieved according to the invention by a novelcrystalline form of CCDC which is referred to as modification Ahereinbelow.

BRIEF DESCRIPTION OF DRAWINGS

A characteristic X-ray powder diffractogram of the CCDC of modificationA is shown in FIG. 1.

A characteristic differential thermodiagram CCDC of the modification Ais shown in FIG. 2.

An infrared spectrum of CCDC of the modification A, measured in KBr, isshown in FIG. 3.

An X-ray powder diffractogram of the CCDA obtained by the ComparativeExample at page 5 is shown in FIG. 4.

The invention accordingly provides the crystalline modification A ofCCDC which is characterized by an X-ray powder diffractogram having thereflection signals (2 theta) of high and medium intensity (>30% relativeintensity) listed in Table 1 below.

TABLE 1 X-ray powder diffractogram of CCDC of the modification A 2 θ (2theta)  6.70  8.92 12.44 13.66 15.96 17.60 21.42 21.78 28.97

A characteristic X-ray powder diffractogram of the modification A isalso shown in FIG. 1.

Moreover, the CCDC modification A according to the invention differsfrom other forms of CCDC in a number of further properties. Theseproperties, on their own or together with the other parameters, mayserve for characterizing the CCDC modification A according to theinvention.

The CCDC of the modification A is, inter alia, characterized by amelting point, determined with the aid of differential thermoanalysis(DTA), of from 249 to 252° C. A characteristic differentialthermodiagram is shown in FIG. 2.

CCDC of the modification A is also characterized in that it has aninfrared spectrum, measured in KBr, as shown in FIG. 3.

CCDC of the modification A is furthermore characterized in that it isobtainable by the preparation process given below. The crystalmodification A of CCDC is obtained by dissolving CCDC of unknownmodification or amorphous CCDC in hot water or a hot alcohol/watermixture, subsequently adding an alcohol and, after cooling to roomtemperature, isolating the precipitated solid.

In a preferred embodiment, the alcohol used is ethanol or isopropanol.

CCDC of the crystal modification A is surprisingly stable and does notchange into another crystal modification or the amorphous form, even onprolonged storage. In addition, compared with amorphous CCDC, themodification A tends to absorb much less water from the atmosphere. Forthese reasons, it is highly suitable for preparing tablets or othersolid formulations. Owing to its stability, it gives these formulationsthe desired long-lasting storage stability. Using the crystalmodification A, it is therefore possible to prepare, in a defined andtargeted manner, stable solid preparations of CCDC.

CCDC of the crystal modification A is highly active against pathogenicbacteria in the field of human or veterinary medicine. Its broad area ofuse corresponds to that of CCDC.

The X-ray powder diffractogram for characterizing the crystalmodification A of CCDC was obtained using a transmission diffractometerSTADI-P with a location-sensitive detector (PSD2) from Stoe.

The melting point of the differential thermoanalysis was obtained usingthe DSC 820 unit from Mettler-Toledo. Here, the sample of CCDC of thecrystal modification A was heated exposed to the atmosphere in analuminium crucible at 10 K/min.

The KBr IR spectrum was obtained using the FTS 60A unit from Biorad.

The examples below illustrate the invention without limiting it. Thesolvent/base systems used in the examples below are particularlypreferred.

Comparative Example

A mixture of 3.07 g of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro4-oxo-3-quinolinecarboxylic acid, 1.39 g of(1S,6S)-2,8-diazabicyclo[4.3.0]nonane, 2.24 g of (hot precipitation)1,4-diazabicyclo[2.2.2]octane (DABCO), 29.5 ml of dimethylformamide and29.5 ml of acetonitrile is stirred at room temperature for 16 hours. Thereaction mixture is concentrated at a bath temperature of 60° C. using arotary evaporator, and the residue is taken up in 10 ml of water. Theresulting solution is adjusted to pH 7 using dilute hydrochloric acid,and the solid is filtered off. The filtrate is extracted three timesusing 20 ml of dichloromethane each time. The organic phase is driedover sodium sulphate and filtered and the filtrate is concentrated at abath temperature of 60° C. using a rotary evaporator. This gives 2.4 gof a light-brown solid which has the X-ray powder diffractogram shown inFIG. 4 and is therefore predominantlyamorphous.

At a relative atmospheric humidity of 95% (established using a saturatedsolution of Na₂HPO₄×12 H₂O with sediment in water), the solid obtainedaccording to this procedure absorbs approximately 17% by weight of waterwithin one day.

Example 1

617 g of CCDC of any modification are dissolved in 6170 ml ofchloroform. 100 g of sodium sulphate are added, the mixture is stirredfor 5 minutes and then filtered through 50 g of kieselguhr, which isthen washed with 100 ml of chloroform. The solvent is distilled off on arotary evaporator up to a residual pressure of 10 mbar, resulting in aglass-like residue. 740 ml of water and 740 ml of ethanol are added tothis residue, and the mixture is heated at 60° C. until the entireresidue has been dissolved. This solution is then added to 17 liters ofboiling ethanol. This mixture is boiled for a further 5 minutes and thencooled to 35° C. over a period of one hour. The precipitated crystalsare filtered off with suction and dried at 20° C. for approximately 16hours and then at 30° C. under reduced pressure until the weight remainsconstant.

This gives 530 g of a solid which has the X-ray powder diffractogramshown in FIG. 1, the differential thermodiagram shown in FIG. 2 and theIR spectrum shown in FIG. 3.

At a relative atmospheric humidity of 95% (established using a saturatedsolution of Na₂HPO₄×12 H₂O with sediment in water), the solid obtainedaccording to this procedure absorbs approximately 3% by weight of waterwithin one day.

Example 2

2 g of CCDC of unknown modification are dissolved in 4 ml of water. 4 mlof isopropanol are added, the reaction mixture is slowly heated withstirring and a further 32 ml of isopropanol are then added. Theresulting clear solution is brought to the boil. The solution becomesturbid, and within a short period of time, crystals precipitate out.After 3 minutes at reflux, the heating is removed and the mixture isallowed to stand without stirring for 3 to 4 hours. The solid is thenfiltered off with suction, washed with isopropanol and dried in theatmosphere until the weight remains constant. This gives 1.54 g of asolid which has an X-ray powder diffractogram identical to that shown inFIG. 1, a differential thermodiagram identical to that shown in FIG. 2and an IR spectrum identical to that shown in FIG. 3.

What is claimed is: 1.8-Cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro4-oxo-3-quinolinecarboxylicacid (CCDC) of the crystal modification A, having an X-ray powderdiffractogram with the following reflection signals (2 theta) of highand medium intensity 2 θ (2 theta)  6.70  8.92 12.44 13.66 15.96 17.6021.42 21.78  28.97.

2.8-Cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (CCDC) of the crystal modification A, having an X-ray powderdiffractogram with the following reflection signals (2 theta) of highand medium intensity 2 θ (2 theta)  6.70  8.92 12.44 13.66 15.96 17.6021.42 21.78 28.97

and a melting point, determined by DTA, of from 249° C. to 252° C. 3.8-Cyano-1-cyclopropyl-7-(l1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (CCDC) of the crystal modification A as recited in claim 1 or 2,obtainable by dissolving CCDC of unknown modification or amorphous CCDCin water or a water/alcohol mixture, followed by hot precipitation afterthe addition of alcohol.
 4. Process for preparing CCDC of themodification A according to claim 1, comprising dissolving CCDC ofunknown modification or amorphous CCDC in water or a water/alcoholmixture, adding alcohol to the resulting mixture and hot precipitatingthe CCDC of the modification A.
 5. Process for preparing CCDC of themodification A according to claim 4, wherein the alcohol used is ethanolor isopropanol.
 6. A method of preparing a composition comprisingformulating CCDC of the modification A according to claim
 1. 7. Aprocess for combating bacteria comprising admiunistering to the manualin need thereof amount of CCDC of the modification A according toclaim
 1. 8. A method of preparing a composition comprising formulatingCCDC of the modification A according to claim
 2. 9. A method ofpreparing a composition comprising formulating CCDC of the modificationA according to claim
 3. 10. A process for combating bacteria comprisingadministering to a manual in used thereof an antibacterial amount ofCCDC of the modification A according to claim
 2. 11. A process forcombating bacteria comprising administering to a manual in need thereofan antibacterial amount of CCDC of the modification A according to claim3.